Chromenone derivatives

Abstract

Novel compounds of the formula I in which R 1 , R 2 , R 3 and Het are as defined herein, which are inhibitors of tyrosine kinases and/or Raf kinases and can be employed for the treatment of tumors, for neuroprotection and for protection of the stress proteins of the skin.

1. A method of treating a disease in which inhibition, regulation and/or modulation of PKB kinase, RAF kinase or Tie-2 tyrosine kinase signal transduction plays a role,
 comprising administering to a patient in need thereof an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising said compound or said salt thereof and a pharmaceutically acceptable carrier 
 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  is —OH or —OA, 
       R 2  is H, —OH, —OA, phenoxy, —O—CO-A, —OSO 3 H, —OSO 3 A, —OSO 2 A or Hal, 
       R 3  is H, 
       R 1  and R 2  together are alternatively methylenedioxy or ethylenedioxy, 
       Het is chromen-2-onyl, benzothiazolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, quinolyl or isoquinolyl, each of which is unsubstituted or mono- or disubstituted by Hal and/or A, and 
       A is unbranched or branched alkyl having 1-6 carbon atoms, where 1-5 H atoms may be replaced by F. 
     
     
       2. A method according to  claim 1 , wherein the kinase whose transduction is affected is Tie-2 tyrosine kinase or Raf kinase. 
     
     
       3. A method according to  claim 1 , wherein Tie-2 tyrosine kinase is inhibited. 
     
     
       4. A method according to  claim 3 , wherein the disease treated is a solid tumour. 
     
     
       5. A method according to  claim 4 , wherein the solid tumour is a brain tumour, tumour of the urogenital tract, tumour of the lymphatic system, stomach tumour, laryngeal tumour or lung tumour. 
     
     
       6. A method according to  claim 4 , wherein the solid tumour is monocytic leukaemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma or breast carcinoma. 
     
     
       7. A method according to  claim 4 , wherein the disease treated is affected by angiogenesis. 
     
     
       8. A method according to  claim 3 , further comprising administering 1) an oestrogen receptor modulator, 2) an androgen receptor modulator, 3) a retinoid receptor modulator, 4) a cytotoxic agent, 5) an antiproliferative agent, 6) a prenyl-protein transferase inhibitor, 7) an HMG-CoA reductase inhibitor, 8) an HIV protease inhibitor, 9) a reverse transcriptase inhibitor or 10) an angiogenesis inhibitor. 
     
     
       9. A method according to  claim 3 , further comprising administering radiotherapy. 
     
     
       10. A method according to  claim 1 , wherein the disease is treated, mediated and/or propagated by inhibition, regulation and/or modulation of Raf kinase. 
     
     
       11. A method according to  claim 10 , wherein the Raf kinase is A-Raf, B-Raf or Raf-1. 
     
     
       12. A method according to  claim 10 , wherein the disease treated is a hyperproliferative disease. 
     
     
       13. A method according to  claim 10 , wherein the disease treated is cancerous. 
     
     
       14. A method according to  claim 10 , wherein the disease is brain cancer, lung cancer, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, hepatic cancer, renal cancer, colorectal cancer, breast cancer, head cancer, neck cancer, oesophageal cancer, gynaecological cancer, thyroid cancer, lymphoma, chronic leukaemia or acute leukaemia. 
     
     
       15. A method for the treatment of a disease facilitated by PKB kinase, RAF kinase or Tie 2 tyrosine kinase signal transduction in a patient comprising administering to the patient a compound which inhibits signal transduction by PKB kinase, RAF kinase or Tie 2 tyrosine kinase in the patient,
 comprising administering to a patient in need thereof an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising said compound or said salt thereof and a pharmaceutically acceptable carrier 
 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  is —OH or —OA, 
       R 2  is H, —OH, —OA, phenoxy, —O—CO-A, —OSO 3 H, —OSO 3 A, —OSO 2 A or Hal, 
       R 3  is H, 
       R 1  and R 2  together are alternatively methylenedioxy or ethylenedioxy, 
       Het is chromen-2-onyl, benzothiazolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, quinolyl or isoquinolyl, each of which is unsubstituted or mono- or disubstituted by Hal and/or A, and 
       A is unbranched or branched alkyl having 1-6 carbon atoms, where 1-5 H atoms may be replaced by F.